ME1介导的代谢重组在基底样乳腺癌的作用和机制研究

Basal-like Breast Cancer (BLBC) is associated with an aggressive clinical history, development of recurrence, distant metastasis and shorter patient survival. BLBC contains abundant EMT markers and possesses many cancer stem cell-like characteristics, but the metabolic program associates with these changes remain unknown. Recently, we noticed that ME1, a major NADPH-producing enzyme for the conversion of malate to pyruvate, was significantly elevated in Basal-like breast cancer. We also found ME1 expression was remarkably upregulated by Twist, a master transcription factor that induces EMT through transcriptional repression of E-cadherin. Based on our novel findings, we propose that ME1 provides breast cancer cells with survival and metastasis advantages by mediating metabolic reprogramming; the expression of ME1 represents a high potential for induction of breast cancer metastasis. The objective of this proposal is to characterize the regulation of metabolic reprogramming by Twist-induced ME1, and explore the potential roles of ME1 in tumorigenicity, EMT and metastasis of breast cancer. We will test this hypothesis by determining: (1) whether the expression of ME1 provides a survival and metastatic advantage in BLBC by decreasing oxidative phosphorylation as well as by reducing ROS production; (2) the mechanism of ME1 expression induced by Twist; and (3) the functional importance of the expression of ME1 induced by Twist in vitro and in vivo. Our work will uncover the critical role of ME1 induced by Twist in mediating metabolic switch in BLBC cells. Elucidating the correlation of ME1 with Twist will provide a new understanding of how metabolic reprogramming contributes to EMT and metastasis in BLBC. Our finding will not only provide novel insight into the role of metabolic reprogramming in tumorigenicity, EMT and metastasis of breast cancer cell, but also will assist oncologists in evaluating the risk for metastasis and tailoring strategies for the prevention and treatment of BLBC.

基底样乳腺癌具有增殖活力高、易复发、侵袭和转移能力强、预后差等特征。此外，基底样乳腺癌也含有许多肿瘤干细胞特征和上皮间质转化（EMT）标志物。对于基底乳腺癌发生和转移的代谢调控机制至今尚不清楚。苹果酸酶1（ME1）是一个NADPH合成酶，可以催化苹果酸转变为丙酮酸。我们前期研究发现基底样乳腺癌细胞的ME1表达水平明显高于其它亚型细胞。此外，我们也发现Twist能够显著的提高ME1的表达水平。在本申请项目中，我们将重点研究ME1在肿瘤细胞的代谢重组过程所发挥的作用，明确Twist对ME1表达的调控机制，并深入探讨Twist-ME1轴对基底样乳腺癌发生及转移的影响。系统的研究Twist、ME1、肿瘤发生与转移三者之间的关系，不仅有助于理解代谢重组对基底样乳腺癌的生长转移的影响，也有助于为临床靶向治疗该型乳腺癌提供了新的标记分子与理论基础。

基底样乳腺癌具有增殖活力高、易复发、侵袭和转移能力强、预后差等特征。此外，基底样乳腺癌也含有许多肿瘤干细胞特征和上皮间质转化（EMT）标志物。对于基底乳腺癌发生和转移的代谢调控机制至今尚不清楚。苹果酸酶1（ME1）是一个NADPH合成酶，可以催化苹果酸转变为丙酮酸。我们研究发现基底样乳腺癌细胞的ME1表达水平明显高于其它亚型细胞。Twist1能够显著的提高ME1的表达水平。此外，我们证实了ME1通过促进三羧酸循环向有氧糖酵解的转变，这种转变对乳腺癌发生发展有促进作用。我们还证实ME1高表达与肿瘤级别、肿瘤大小呈正相关，与化疗敏感性及患者生存率呈负相关。系统的研究ME1、肿瘤发生与转移的关系，不仅有助于理解代谢重组对基底样乳腺癌的的影响，也有助于为临床靶向治疗该型乳腺癌提供了新的标记分子与理论基础。